Lower urinary tract disorder is a general term referring to disorders of lower urinary tract functions. Lower urinary tract symptoms caused by lower urinary tract disorders are mainly classified into three groups, i.e., storage symptoms such as pollakisuria and urinary urgency, voiding symptoms such as slow stream and splitting of the urine stream, and post micturition symptoms such as feeling of incomplete emptying and post micturition dribble. Lower urinary tract symptoms also include lower urinary tract pain such as painful urination, bladder pain, and urethral pain, detrusor overactivity, and voiding difficulty. Hematuria is sometimes observed with lower urinary tract disorders. Diseases which are causes of the lower urinary tract disorders include hyperplasia of prostate, prostatitis, prostatodynia, bladder neck sclerosis, overactive bladder, interstitial cystitis, and painful bladder syndrome.
Among the aforementioned diseases, interstitial cystitis is an intractable disease whose symptoms include pollakisuria, increased desire to urinate, urinary urgency, bladder discomfort and bladder pain, in the absence of urinary tract infection or other obvious pathologic condition. Causes of interstitial cystitis have been considered to be mast cell activation, a defect of glycosaminoglycan layer, inhibition of cell proliferation at the urinary tract epithelium, autoimmune, neurogenic inflammation, nitric oxide metabolism, toxic materials, hypoxia and the like, but an apparent cause has not yet been elucidated. Although interstitial cystitis is sometimes accompanied with non-specific chronic inflammation of the bladder, anti-inflammatory drugs such as steroids are not effective for said disease or animal models of the disease. Therefore, it is considered that inflammation itself does not cause interstitial cystitis symptoms such as pollakisuria. As drug therapies for interstitial cystitis, antihistaminic drug, antidepressants, cimetidine, antibiotics, steroids, pentosan polysulfate and the like have been used. However, none of these drugs provides an effective therapeutic method, and therefore, development of a medicament that can achieve high therapeutic effectiveness has been strongly desired.
Retinoic acid (vitamin A acid), an active metabolite of vitamin A, has extremely important physiological functions, e.g., inducing differentiation of immature cells under development processes toward mature cells having specific functions, enhancement of cell proliferation, and life support action. It has been revealed that various vitamin A derivatives synthesized so far also have similar physiological functions, for example, the benzoic acid derivatives disclosed in Japanese Patent Unexamined Publication (KOKAI) Nos. (Sho)61-22047/1986 and (Sho)61-76440/1986, and the compounds described in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, p. 2182. “Retinoids” is a general term for retinoic acid and the aforementioned compounds having retinoic acid-like biological activities.
For example, it was proved that all-trans retinoic acid binds as a ligand to the retinoic acid receptor (RAR) present in cellular nucleus, which belongs to the intranuclear receptor super family (Evans, R. M., Science, 240, p. 889, 1988), and regulates proliferation and differentiation of animal cells or cellular mortalities through induction of the activity as a transcription factor (Petkovich, M., et al., Nature, 330, pp. 444-450, 1987). In addition, the existence of retinoid X receptor (RXR) has been elucidated whose ligand is 9-cis-retinoic acid. The retinoid X receptor has been revealed to participate in the expression of the activities of the retinoic acid by inducing or suppressing the transcription of a target gene by forming a homo-dimer or a heterodimer between the retinoic acid receptor (Mangelsdorf, D. J. et al., Nature, 345, pp. 224-229).
It has also been suggested that the aforementioned compounds having the retinoic acid-like biological activities, e.g., 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid: Am80, also bind to RAR in similar manners to retinoic acid to exhibit their physiological actions (see, Hashimoto, Y., Cell Struct. Funct., 16, pp. 113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Commun., 166, pp. 1300-1307, 1990). Experimentally by using animals and clinically, these compounds were found to be useful for therapeutic and preventive treatments of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bone diseases, leukemia and certain types of cancer.
As for relation of retinoids and lower urinary tract disorders, it was reported that no correlation was observed between lower urinary tract symptoms and blood concentration of Vitamin A (Urology, 64, pp. 504-509, 2004), and a therapeutic effect of retinoids on lower urinary tract disorders has not been reported so far.    Patent Document 1 Japanese Patent Unexamined Publication (KOKAI) No. (Sho) 61-22047    Patent Document 2 Japanese Patent Unexamined Publication (KOKAI) No. (Sho) 61-76440    Non-patent Document 1 Journal of Medicinal Chemistry, 31, No. 11, p. 2182, 1988    Non-patent Document 2 Cell Struct. Funct., 16, pp. 113-123, 1991    Non-patent Document 3 Biochem. Biophys. Res. Commun., 166, pp. 1300-1307, 1990    Non-patent Document 4 Urology, 64, pp. 504-509, 2004